Device for the treatment of sleep apnea syndrome in a patient by kinesthetic stimulation

ABSTRACT

A device for treating sleep apnea in a patient through stimulation. The device includes a generator configured to produce stimulation pulses, a stimulator that receives the stimulation pulses produced by the generator and delivers stimulation to the patient, and a controller. The controller is configured to determine a sleep state of the patient, adaptively control the generator based on the sleep state where the sleep state includes a plurality of sleep stages, and modulate a stimulation energy of the stimulation pulses produced by the generator based on the sleep stage of the patient.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of and priority to French PatentApplication No. 14/51061, filed Feb. 11, 2014, which is herebyincorporated by reference herein in its entirety.

BACKGROUND

The invention relates to the diagnosis and treatment of sleep disorders.It more particularly relates to the use for this purpose of a deviceknown as “kinesthetic stimulation” device, that is to say a device withexternal sensory stimulation of the patient by methods of a vibrator incontact with skin in a sensitive, specific area of the body of thepatient. Enabling this vibrator has the effect of locally excitingcutaneous endings or mechanical receptors in the skin and triggering aresponse of the autonomic nervous system of the patient, withsympathetic predominance (hereinafter “autonomic response”).

Autonomic response to sympathetic activation is observable on majormodulator effects of cardiac activity, for example:

-   Chronotropic effect: increased heart rate, or decrease in RR    intervals;-   Inotropic effect: increased cardiac contractility.

This autonomic response is also observed on the peripheralvasoconstriction, which is increased in case of sympathetic autonomicactivation. This phenomenon may be implemented notably with the devicedescribed in US 2013/0102937 A1, which proposes to treat hypertension byappropriate stimulation of baroreceptors or nerves, especially duringperiods when the patient is asleep. The stimulation is triggered whenthe patient is known to be dormant, then maintained at a constant level.In addition to these effects on cardiac activity, sympathetic activationcauses responses in the respiratory system or in the central nervoussystem (autonomic awakenings).

This is a noninvasive method which is applicable for a number of sleepdisorders as an alternative to conventional therapeutic approaches basedon the application of a continuous positive airway pressure through aface mask (processing named CPAP), the use of a mandibular protrusionsplint and/or electrical stimulation of the hypoglossal nerve, whichinvolves an implant such as a pacemaker.

In particular, the respiratory disease known as “sleep apnea syndrome”(SAS) is characterized by the frequent occurrence (at least 10 to 20times per hour) of apneas during a sleep phase of the patient, an“apnea” (or pause in breathing) being defined as a temporary cessationof the respiratory function for a duration of more than 10 seconds. Itmay also be characterized by the occurrence in the same conditions ofhypopnea, a “hypopnea” being defined as a significant decrease (butwithout interruption) of the respiratory rate, typically a decrease ofover 50% compared to an earlier reference mean. In the following of thedescription, we will not distinguish between these two phenomena, areference to “apneas” being meant to also include hypopneas.

This condition reached more than 4% of the population and over 50% ofpatients with heart failure. To protect the individual againstasphyxiation due to the decrease of oxygen concentration in the bloodduring the interruption or reduction of the respiratory rate, the bodyadapts but with a deleterious effect on sleep, causing unconsciousmicro-awaking. Daytime sleepiness, with loss of attention and increasedrisk of accident, follows in phase of awakening. Furthermore, severalstudies of patients with SAS have shown greater incidence of disorderssuch as arterial hypertension, ventricular arrhythmias, myocardialinfarction and heart failure.

For stopping the apnea episodes with a stimulation therapy,US2008/0009915 A1 proposes an acoustic stimulation therapy,US2004/0215236 A1 a vestibular stimulation therapy, WO2009/154458 A1 anelectrical stimulation therapy and the U.S. Pat. No. 4,813,427A theapplication of a gas in parallel to tactile stimulation therapy.Kinesthetic stimulation has been proposed in the past to minimize orstop the episodes of sleep apnea in adults or in the newborn, asdescribed for example in the WO 2007/141345 A1 (FR 2908624 A1).

These techniques are also described in the articles of Pichardo R., etal., “Validation of a Vibrotactile Stimulation System to Treat Apnea ofPrematurity”, Proceedings of the IEEE 27th annual NortheastBioengineering Conference, University of Connecticut, Storrs, Conn.(2001) 13-14, and Beuchée A. et al., “Stimulateur kinesthésiqueautomatisé asservi à la détection d'apnées-bradycardies chez lenouveau-né prématuré”, ITBM-RBM, 28(2007) 124-130.

The first drawback of these stimulation methods is the responsevariability according to the patient, or even depending on the patient'scondition and in particular the sleep state. This variability mayrequire complex initialization methods of the system to adapt to thepatient parameters. The second drawback is a phenomenon of habituation,which requires therapy to constantly evolve to keep it effective. Somesystems describe a randomized variation of the therapy, which then maybe poorly reproducible. The third drawback is the risk of waking thepatient. Indeed, the stimuli can generate awakenings in turn responsiblefor the sleep destructuration. These awakenings induce a loss of much ofthe benefit of therapy. But few methods take into account this risk, ordescribe an impractical method for example based on the detection ofsleep states by analyzing the EEG, a technique which is impractical inroutine practice or at home.

SUMMARY

Kinesthetic stimulation therapy of this disease includes, on detectionof an apnea or hypopnea episode, generating appropriate stimulationwhich can cause an autonomic response in the patient that may triggerrespiratory modification, for example, a respiratory recovery or anincrease in respiration that will end apnea. Thus, according to variousembodiments, there is disclosed a technique to interrupt episodes ofapnea by kinesthetic stimulation, by generating a sufficient but notexcessive autonomic response adapted to stop the apnea, in order tolimit the appearance of micro-awakenings.

In this regard, clinical studies have shown that for a given stimulationenergy, the autonomic response is dependent on the sleep stage (slowsleep stages I to IV and REM sleep). See for example Hord D. et al.,“The Evoked Heart Rate Response during Sleep”, Psychophysiology, 3:46-54(1966), which examines various parameters of the change in autonomicresponse of patients when sound stimuli are emitted close to their earat different times of sleep.

According to an exemplary embodiment, in view of the relationshipbetween the sleep stage and the autonomic response, the kinestheticstimulation therapy is directed to i) detecting the current sleep stageand ii) controlling the kinesthetic stimulation energy according to thecurrent sleep stage thus detected at the time when the stimulation isapplied, to generate sufficient autonomic response to stop apnea but thelevel of which is low enough to prevent or at least limit the appearanceof micro-awakenings.

According to various embodiments, a first aspect of a method toautomatically determine the current sleep stage of the patient includes(but not limited to) the application for a kinesthetic stimulationtherapy to the appropriate energy level, as just exposed, or any othertherapy (cardiac pacing, neuromuscular stimulation, etc.),differentially depending on the current sleep stage at the time ofapplication of the therapy. This discrimination of sleep stages can alsobe used just for diagnostics. The discrimination can be used to providea less expensive and more convenient alternative to polysomnography(PSG). The discrimination can be used to analyze sleep patterns anddiagnose certain sleep disorders.

The sleep stages may be manually, sometimes automatically, evaluatedfrom electroencephalographic recordings (EEG) signals collected duringpolysomnography, by analyzing the amplitude and frequency of at leastthree channels of EEG signals. The difficulty is related to the placingof many EEG sensors, which makes such an examination not feasible inroutine. Other methods of detection of sleep stages have been proposedusing cardiopulmonary Holter recordings, from the variability of sinusrhythm, etc., but these methods do not allow to differentiate betweenwakefulness and sleep state, or between REM state (REM) and non-REMstate (slow wave sleep), and they do not distinguish all sleep stages,especially to discriminate between the different slow wave sleep stages,from I (drowsiness) to IV (deep sleep).

Automatic discrimination of sleep stages may in particular allow abetter diagnosis of sleep, because during PSG, the patient poorly sleepsinsofar as he/she is in a hospital room and is covered with all kinds ofsensors. Therefore there is a need for a lighter and automatic systemallowing both the patient to sleep better and to provide the physicianwith a faster and less expensive, easily and routinely applicablemethod.

According to various embodiments, a second aspect relates to the use ofthe knowledge of the sleep current stage—whether it has been determinedin accordance with the first aspect or by another method—to applykinesthetic stimulation therapy at an appropriate energy level. Theenergy level is differentiated based on the current sleep stage at thetime of application of the therapy in order to generate sufficientautonomic response to stop apnea but the level being low enough toprevent or at least limit the appearance of micro-awakenings.

According to an exemplary embodiment, the device/system provides fordiscrimination of the successive sleep stages of a patient. This devicemay be similar to that shown, for example, from the aforementionedarticles from Pichardo et al. and Beuchée et al. The device includes agenerator capable of producing controlled kinesthetic stimulation pulsesbursts; at least one kinesthetic effector adapted to be applied to anexternal skin site of the patient, and including a vibratingelectromechanical transducer adapted to receive the pulses produced bythe generator; methods for measuring at least one control parameter ofthe current autonomic activity of the patient; and detector methods,adapted to determine a sleep state of the patient.

The device further includes, to operate the discrimination of thesuccessive sleep stages, methods of analysis of the sleep, conditionallyactivated in the presence of only a sleep state determined by thedetection methods and including: control methods capable of controllingthe activation of the generator to trigger the production of akinesthetic pulses burst; methods adapted to determine, according tosaid measurement of at least one control parameter for the currentpatient's autonomic activity, a variation of this control parametersubsequent to said production of the kinesthetic pulses burst; andevaluator methods suitable for determining a patient's response toautonomic kinesthetic stimulation in accordance with said variation.

According to exemplary embodiments, the sleep analysis methods includemethods of discrimination, capable of determining, following thekinesthetic stimulation produced by the activation of the generator bythe control methods, and in accordance with the determined autonomicresponse by the evaluator methods, the sleep stage of the patient from aplurality of predetermined stages of the group including: Slow WaveSleep I, Slow Wave Sleep II, Slow Wave Sleep III, Slow Wave Sleep IV andREM sleep.

According to various embodiments:

-   -   The control parameter of the current autonomic activity of the        patient is the current heart rate of the patient, or a parameter        of the group including: respiratory rate; blood oxygen        saturation; and derivative parameter from a phonocardiographic        waveform signal or an endocardial acceleration signal;    -   The apparatus further includes initialization methods adapted,        on determination of a sleep state by the detection methods, to        establish the level of at least one predetermined parameter of        the pulses burst of kinesthetic stimulation, this stimulation        parameter being a parameter of the group including: delivered        energy; duration of the stimulation pulses burst; pulse        repetition frequency; and unitary duration of the pulses;    -   The initialization methods include test methods including:        methods adapted to initialize the stimulation parameter level to        a default value; methods able to compare the current autonomic        response determined by the evaluator methods to a first        threshold; and methods adapted, if the current autonomic        response is below the first threshold, to iteratively change        step by step the stimulation parameter level until crossing of        the first threshold;    -   The device further includes methods adapted to reiteratively        activate the methods of analysis of sleep and including: methods        adapted to compare the current autonomic response with a        previous stored value of the autonomic response; and methods        adapted to re-activate the discriminating methods if the        difference between the current autonomic response and the        previous autonomic response exceeds a second predetermined        threshold;    -   The discriminating methods are adapted to determine the sleep        stage in a relative manner, with respect to a previous stored        level of sleep stage of the patient, based on the determined        difference between the current autonomic response and the stored        previous autonomic response;    -   The discriminating methods are deterministic methods, able to        raise the level of sleep stage in case of reduction of the gap        between the current autonomic response and the previous        autonomic response, and vice versa, or stochastic methods        implementing an automaton with a finite number of states whose        transitions are defined by a Markov or semi-Markov process.

According to the aforementioned second aspect, the invention provides adevice for treatment of sleep apnea syndrome in a patient by kinestheticstimulation, similar to that, for example, in US 2013/0102937 A1. Thedevice includes a generator capable of producing kinesthetic stimulationcontrolled pulses bursts; at least one kinesthetic effector adapted tobe applied to an external skin site of the patient, and including avibrating electromechanical transducer adapted to receive the pulsesproduced by the generator and to provide given kinesthetic stimulationenergy; and detector methods, adapted to determine a sleep state of thepatient. The device further includes methods for adaptively controllingthe generator, conditionally activated only in the presence of a sleepstate determined by the detection methods.

According to exemplary embodiments, the methods of adaptive control ofthe generator include: discriminating methods, able to determine thesleep stage of the patient from a plurality of predetermined stages ofthe group including: Slow Wave Sleep I, Slow Wave Sleep II, Slow WaveSleep III, Slow Wave Sleep IV and REM sleep; and modulating methodscapable of changing the energy level of kinesthetic stimulation burstsproduced by the generator according to the sleep stage of the patientdetermined by discriminating methods.

According to various embodiments:

-   -   The modulating methods may be adapted to increase the        stimulation energy for a higher sleep stage, and vice versa;    -   The device further includes methods for detecting the occurrence        of an apnea or hypopnea episode and methods adapted to        conditionally activate the generator upon detection of an        episode of apnea or hypopnea and possibly methods for detecting        the end of the episode of apnea or hypopnea and methods able to        disable the generator to detect the end of the episode of apnea        or hypopnea;    -   The modulating methods include methods capable of applying a        predetermined stimulation energy increment/decrement according        to each of the predetermined sleep stages;    -   The modulating methods include a lookup table assigning a        predetermined stimulation energy level to each of the        predetermined sleep stages, and optionally methods adapted for        initializing, upon determination of a sleep state by the        detection methods, to establish the energy level values of the        correspondence table;    -   The device further includes evaluator methods, capable of        determining an autonomic patient's response to kinesthetic        stimulation depending on the variation, following the production        of the pulses burst, of a control parameter of the current        autonomic activity of the patient;    -   The control parameter of the current autonomic activity of the        patient is the patient's current heart rate or a parameter of        the group comprising: breath rate; blood oxygen saturation; and        derivative parameter of a phonocardiographic signal or of an        endocardial acceleration signal;    -   The initialization methods include, for determining the energy        level value of corresponding to the first sleep stage: methods        able to initialize the stimulation energy to a predetermined        default minimum value; methods able to compare the current        autonomic response determined by the evaluator methods to a        first threshold; methods capable, if the current autonomic        response is below the first threshold, to step by step and        iteratively change the stimulation energy until crossing of the        first threshold; and methods, for the first sleep stage, for        storing the value of the stimulation energy obtained after        crossing the threshold;    -   The device further includes methods suitable for calculating and        storing stimulation energy values corresponding to the sleep        stages following the first stage, according to the stimulation        energy value stored for the first stage;    -   The discriminating methods are adapted to determine the current        sleep stage based on the autonomic response determined by the        evaluator methods.

One embodiment relates to a device for treating sleep apnea in a patientthrough stimulation. The device includes a generator configured toproduce stimulation pulses, a stimulator that receives the stimulationpulses produced by the generator and delivers stimulation to thepatient, and a controller. The controller is configured to determine asleep state of the patient, adaptively control the generator based onthe sleep state where the sleep state includes a plurality of sleepstages, and modulate a stimulation energy of the stimulation pulsesproduced by the generator based on the sleep stage of the patient.

According to an exemplary embodiment, the generator is activated by thecontroller in the presence of the sleep state. The plurality of sleepstages include slow-wave sleep I, slow-wave sleep II, slow-wave sleepIII, slow-wave sleep IV, and REM sleep. In some embodiments, thecontroller is configured to increase the stimulation energy as the sleepstage increases, and decrease the stimulation energy as the sleep stagedecreases.

In some embodiments, the device includes a sensor configured to detectan occurrence of an apnea or hypopnea episode. The controller activatesthe generator upon detection of the apnea or hypopnea episode anddisables the generator on the detection of the end of the apnea orhypopnea episode.

In various embodiments, the controller modulates the stimulation energybased on a predetermined increment/decrement for each of the pluralityof sleep stages. In other embodiments, the controller utilizes acorrespondence table to assign the stimulation energy to each of theplurality of sleep stages.

In some embodiments, the controller determines a response of the patientto the stimulation based on the variation of a biological parameter ofthe patient following the delivery of the stimulation to the patient.The biological parameter may be at least one of a current heart rate ofthe patient, a respiratory rate, a blood oxygen saturation, and aderivative parameter of a phonocardiographic signal or an endocardialacceleration signal. In one embodiment, the controller is configured todetermine a current sleep stage based on the response of the patient tothe stimulation. In some embodiments, the controller is configured todetermine the stimulation energy that corresponds to a first sleep stageby initializing the stimulation energy to a predetermined defaultminimum value, comparing a current response of the patient to a firstthreshold, iteratively changing the stimulation energy until thestimulation energy exceeds the first threshold, and storing thestimulation energy for the first sleep stage. The controller may thendetermine and store the stimulation energy corresponding to each of theplurality of sleep stages following the first sleep stage based on thestimulation energy stored for the first sleep stage.

Another embodiment relates to a method of treating sleep apnea in apatient through stimulation. The method includes determining, by acontroller, a sleep state of the patient, wherein the sleep stateincludes a plurality of sleep stages; modulating, by the controller, astimulation energy of stimulation pulses produced by a generator basedon the sleep stage of the patient; and delivering, by a stimulator,stimulation to the patient by receiving the stimulation pulses from thegenerator.

According to an exemplary embodiment, the generator is activated by thecontroller in the presence of the sleep state. The plurality of sleepstages include slow-wave sleep I, slow-wave sleep II, slow-wave sleepIII, slow-wave sleep IV, and REM sleep. In one embodiment, thecontroller is configured to increase the stimulation energy as the sleepstage increases, and decrease the stimulation energy when the sleepstage increases.

In one embodiment, the method further includes detecting, by a sensor,an occurrence of an apnea or hypopnea episode; and activating, by thecontroller, the generator upon detection of the apnea or hypopneaepisode. Additionally, the method may include detecting, by the sensor,an end of the apnea or hypopnea episode; and disabling, by thecontroller, the generator upon detection of the end of the apnea orhypopnea episode.

In various embodiments, the method includes determining, by thecontroller, a response of the patient to the stimulation based on thevariation of a biological parameter of the patient following thedelivery of the stimulation to the patient. The biological parameter maybe at least one of a current heart rate of the patient, a respiratoryrate, a blood oxygen saturation, and a derivative parameter of aphonocardiographic signal or an endocardial acceleration signal. In oneembodiment, the method includes determining, by the controller, acurrent sleep stage based on the response of the patient to thestimulation. In another embodiment, the method includes determining, bythe controller, the stimulation energy that corresponds to a first sleepstage by initializing the stimulation energy to a predetermined defaultminimum value; comparing a current response of the patient to a firstthreshold; iteratively changing the stimulation energy until thestimulation energy exceeds the first threshold; and storing thestimulation energy for the first sleep stage. In some embodiments, thecontroller is configured to determine and store the stimulation energycorresponding to each of the plurality of sleep stages following thefirst sleep stage based on the stimulation energy stored for the firstsleep stage.

Still another embodiment relates to a device for treating sleep apnea ina patient. The device includes a generator configured to producestimulation pulses; a stimulator that receives the stimulation pulsesproduced by the generator and delivers stimulation to the patient; and acontroller configured to modulate a stimulation energy of thestimulation pulses produced by the generator based on a state of thepatient during a sleep apnea or hypopnea episode.

DESCRIPTION OF THE FIGURES

Further features, characteristics and advantages of the presentinvention will become apparent to a person of ordinary skill in the artfrom the following detailed description of preferred embodiments of thepresent invention, made with reference to the drawings annexed, in whichlike reference characters refer to like elements and in which:

FIG. 1 illustrates in general the various successive stages during anight of a patient's sleep, according to an exemplary embodiment.

FIG. 2 schematically illustrates the main components of a kinestheticstimulation system, according to an exemplary embodiment.

FIG. 3 illustrates the variations of the autonomic response to akinesthetic stimulation pulse, this response being evaluated by thechanges in the patient's heart rate, according to an exemplaryembodiment.

FIG. 4 is a diagram illustrating changes in the autonomic response of apopulation of patients at different sleep stages, for the samekinesthetic stimulation energy, according to an exemplary embodiment.

FIG. 5 is a diagram illustrating the proportion of effectivemicro-awakenings in a patient population according to the differentsleep stages, for the same, maximum, kinesthetic stimulation energy,according to an exemplary embodiment.

FIGS. 6 and 7 are flow charts illustrating the different stepsimplemented by the technique of automatic detection of sleep stages,according to an exemplary embodiment.

FIGS. 8 and 9 are diagrams illustrating the various successive stepsimplemented by the servo technique of the invention of the kinestheticstimulation depending on the sleep stage, according to an exemplaryembodiment.

DETAILED DESCRIPTION

FIG. 1 is a diagram showing the different successive sleep stages of apatient during a night's sleep. This sleep is in the form of a series ofcycles during which, from the waking state, the patient enters deeperand deeper cycles of slow wave sleep, from stage I (drowsiness) and II(light sleep) to stages III and IV (deep sleep). Then, usually after ashort return to stage I, the patient enters a stage called REM (RapidEye Movements) sleep, which is characterized by high electrical activityof the brain. The cycles follow each other until the final morningawakening.

The different stages correspond to distinct forms of brain activitycharacterized by specific EEG tracings, recognizable on a recordperformed for example during polysomnography. The course of the sleepperiod of the patient can be interspersed by micro-awakenings. Dependingon the importance of the micro-awakening, the patient may either returnto the same stage, or be down from one stage or directly be boarded to alighter sleep stage.

According to an exemplary embodiment, the kinesthetic stimulation deviceprovides a non-invasive technique for determining, practically in realtime, the current sleep stage of an asleep person without using an EEGexamination (without setting up a multitude of electrodes on thepatient's head) and with minimal or no risk of causing micro-awakeningsthat would be deleterious.

According to various embodiments, the kinesthetic stimulation deviceuses the current sleep stage information to modulate a kinestheticstimulation, in particular so as to end episodes of sleep apnea (orhypopnea), without causing a patient micro-awakening, which would havenegative consequences thereby losing any benefit to reducing apnea.

FIG. 2 schematically illustrates the main components of a system (e.g.,a kinesthetic stimulation system, etc.) used for this purpose. Thissystem includes a Holter recorder 10 connected to various sensors orelectrodes 12, 14, 16, to measure physiological signals, such as heartrate, respiration, oxygen saturation, pulse wave, phonocardiogram, etc.In the following, we will focus mainly on the heart rate, which is asimple parameter to obtain, but this is not restrictive and theinvention may be implemented from other physiological signals collectedfrom the patient.

The system further includes a device for kinesthetic stimulation, with agenerator housing including control box 18 producing pulses applied tokinesthetic stimulation effector 20, for example including of a vibratordisposed in a sensitive region of the skin, typically (in the adults) inthe region of the mastoid bone in the vicinity of the ear. Vibrotactilestimulation applied to the skin by the effector 20 is detected bysensory receptors or mechanoreceptors in the body, and this informationis then transmitted via the sensory nerves to the autonomous centralnervous system.

The effector 20 is for example a transducer of the type C10-100 ofPrecision Microdrives or C2 Tactor of Engineering Acoustics. The type oftransducer may be a transducer that weighs a few grams. The transducermay be capable of emitting vibrations through an integrated vibratorexcited by pulse trains of varying amplitude and duration, typically ata frequency of 250 Hz which is the resonance nominal frequency of thisparticular effector and which is also the frequency at which the skinmechanoreceptors are the most sensitive. Other types of effectors can ofcourse effectively be used.

The control box 18 is controlled by a microcontroller and is configuredfor adjusting the intensity (that is to say, energy) of kinestheticstimulation, by controlled variation of the amplitude and/or the number,the duration and/or the frequency of the pacing pulse trains forming thesignal applied to the effector 20.

The system also includes a housing 22 coupled to the Holter device 10and to the control box 18 via a wire connection or wirelessly 24, 26 inorder to receive data from the Holter device 10, process such data andgenerate control information of kinesthetic stimulation in responsethereto to be transmitted to the control box 18. Alternatively, dataprocessing and control of the control box 18 can be operated from withinthe Holter device 10 and transmitted by a link 28 to the housing 18.

FIG. 3 illustrates, in a given patient, the autonomic response to akinesthetic stimulation, expressed here in terms of changes in heartrate. Such a measure is obtainable via the sensors 12, 14, 16. Theacquisition of the heart rate is not limiting, as the methods may beimplemented with other techniques for quantifying various otherautonomic functions. For example, acquiring the blood pressure or heartsounds (by a phonocardiographic sensor or an endocardial accelerationsensor). The treatment is based on the kinesthetic stimulation appliedin a sensitive area of the skin where the effector 20 may stimulate theautonomic pathways without generating a patient wake. Such an area maypreferably be in the region of the ear. Responses to the stimulation ofthe autonomic system may thus be measured.

Thus, in a study related to patients with SAS data from two PSGrecording nights, they were compared. Randomly, the patient spent anight without kinesthetic stimulation and the other night withkinesthetic stimulation of variable energy and applied at regularintervals. The analysis of these results showed that during nights withstimulation more autonomous micro-awakenings were observed, showing theeffectiveness of the stimulation to activate the autonomic system.Furthermore, the duration of sleep and the duration of the variousstages were not significantly different, indicating that the stimulationdid not result in disintegration of sleep.

Changes in mean heart rate recorded for different levels of kinestheticstimulation applied to the patient at any time during sleep (sleepstages all together) are shown in FIG. 3. At t=0, a burst of stimulationpulses is applied at a given energy level and then stopped at t=5s.Changes in heart rate induced by the stimulation, representative of theautonomic response of the patient, are illustrated by thecharacteristics L1 to L5, which correspond to increasing stimulationenergies.

Typically, the response is biphasic, with an increase in heart ratefollowed by a decrease below the initial baseline, then back to anapproximately stable frequency after twenty cycles after the end of thestimulus. This biphasic response is due to a sympathetic initialactivation due to stimulation (increased heart rate), followed by aparasympathetic compensation response (deceleration curve). It can alsobe observed that the autonomic response, as measured on thecharacteristics L1-L5 by the respective amplitudes REP1-REP5corresponding to the maximum excursion of the heart rate afterstimulation, increases with the energy of this stimulation. Theobservation of the post-stimulation frequency change allows evaluatingthe significance of the autonomic response of the patient.

According to an exemplary embodiment, the treatment provided by thesystem relates to the use of measurable autonomic response for twopurposes:

-   Determination of the sleep stage at a given time; and-   Depending on the sleep stage thus determined, in the case of    detected sleep apnea, the application of kinesthetic stimulation to    stop apnea, but the energy of which is modulated according to the    sleep stage in order not to cause micro-awakenings to the patient.

FIGS. 4 and 5 show, in the form of box-plots, the results of a study ona population of patients on which the importance of the autonomicresponse (measured from the change in heart rate) in response to theapplication of a stimulation pulse kinesthetic was assessed, in variouscircumstances.

In FIG. 4, the vertical axis represents the response rate consideredsignificant in the patient population (e.g. autonomic responsesproducing a heart rate excursion of at least 7 bpm) respectively in thefollowing situations: all sleep stages combined, at the waking state, atthe stage I sleep state, at the stage II sleep state, and at the stageIII sleep state. It should be noted that, in the case of a population ofpatients with respiratory disorders such as sleep apnea, none reachedthe deepest stage IV.

In each of these situations, the central line represents the median ofthe samples and its position in the box is used to assess the symmetryof the data. The lower and upper lines of the box represent theempirical quartiles of order p=¼ (first quartile) and p=¾ (lastquartile). The height of the box is thus the interquartile range. Thetwo lines of the upper and lower limits show the maximum x_(M) andminimum x_(m) values identified for the considered case.

FIG. 4 shows that, for different sleep stages, the importance of theautonomic response following a kinesthetic stimulation decreases as thesleep stage becomes deeper (e.g., increases, etc.). The response duringStage II is lower than that during stage I, and that in stage III (whichhas been reached by only one patient in the study population) is lowerthan that in stage II. In other words, to trigger the same autonomicresponse, for example to stop a single apnea episode, the deeper thesleep stage is, the higher the kinesthetic stimulation energy may be.

In FIG. 5, with the same conventions as before, the micro-awakeningsrate values (determined by a polysomnographic analysis, for example) forthe same sleep stages as those in FIG. 5 are illustrated: all cumulatedsleep stages, stage I, II, III and REM. It is shown that themicro-awakenings rate also depends on the sleep stage. For a givenenergy, the more the sleep stage corresponds to a deep sleep, the morethe micro-awakenings rate decreases. It will be possible to increase theenergy of the kinesthetic stimulation when the sleep stage moves to adeeper level, without the risk of increasing the micro-awakenings. Inother words, the energy of stimulation may be increased when the stageincreases, to ensure the effectiveness of the response; conversely, whena light stage is detected again, the stimulation energy has to bereduced again to avoid causing a wake of the patient.

Determination of the Current Sleep Stage

The determination of the sleep stage of the patient at a given time canbe advantageously used for the therapy of sleep apnea, by appropriatelymodulating kinesthetic stimulation so as not to induce micro-awakenings.This use, however, is not limitative and the detection of sleep stagesmay be used for other therapeutic purposes or other diagnostic purposes,for example, an analysis by simple methods of the course of a night'ssleep in a patient so as to have a record of the successive stages overtime, including whether the patient sleep reaches the deepest, mostrestorative, stages or if an underlying disorder prevents him fromreaching these stages.

With reference to FIGS. 6 and 7, an exemplary implementation of themethod is described, for automatically determining sleep stages based onthe autonomic response to a kinesthetic stimulation. The algorithmbegins with a search for the patient to detect his falling asleepthereof, that is to say, the transition from waking to stage I sleepstate (step 30). This detection of the sleep/wake state of the patientmay be effected for example by a known technique of overlap ofinformation delivered by a physiological sensor (minute ventilationsensor, MV) and an activity sensor (accelerometer sensor, G), withmonitoring of the heart rate. Such a technique is described for examplein EP 1317943 A1 (Sorin CRM S.A.S previously known as ELA Medical).

After falling asleep is detected, the patient is necessarily in stage I.Therefore, an initialization of the autonomic response corresponding tothe first stage is carried out (step 32). This initialization of step 32is described in more detail in FIG. 7. First, the energy of kinestheticstimulation is initialized to the minimum level allowed by thekinesthetic effector stimulation (step 34). A first stimulation isapplied (step 36) and the autonomic response is measured, typically bymeasuring the deflection of the heart rate (HR) following theapplication of the pulse (step 38). If the heart rate variation issufficient (test 40), for example at least 7 bpm, then the appliedenergy is saved and stored for the night and the measured HR response isrecorded as corresponding to the response at the stage I (step 42).Heart rate variation is considered sufficient when it results in avariation of the autonomic response to this stage and to the nextstage—because the autonomic response decreases when the stage increases.

In the case when the observed response is not sufficient, then theenergy is increased by one step (step 44) and the method is repeated(steps 36 and following) with the new stimulation energy. In anotherimplementation, the step 36 may include a group of stimulation in orderto obtain an average autonomic response, or stimulation with twodifferent energies, to verify a variation in frequency between thedifferent energies is obtained.

Referring back to FIG. 6, after the initialization (step 32),periodically or when it is optimal to estimate the current sleep stage,kinesthetic stimulation is applied with the energy that has just beendetermined, and the autonomic response is measured (step 46). If the HRresponse did not significantly change (test 48), no special action isundertaken and the method is repeated periodically (typically every fiveminutes, timing of step 50). In the same method as for step 36, step 46may also include a group of stimuli, the evaluation of the step 48 thenbeing made on the average of the observed responses.

If, however, the level of the autonomic response is significantly varied(test 48) compared to the previously tested and stored level, thisindicates that the sleep stage was probably changed and the new stagehas to be determined (step 52). The new sleep stage is determined bothi) depending on the HR response, that is to say the variation in heartrate observed in response to the stimulation, and ii) according to therecent history sleep stages in of the patient.

To this end, in a first determination approach, it will be consideredthat a reduction in the HR response reveals the transition into a deepersleep, while an increase of this response reveals the transition to alighter sleep. The significance of this decrease/increase may also beused to assess the sleep stage based on data from statistical studies ona patient population, studies that have evaluated typicaldecreased/increased amplitudes according to different transitions: stageI/stage II, stage II/stage III, stage III/stage I, etc. Data from apreliminary study thus showed that the HR response decreases by anaverage of 18% between stage I and II, of 20% between stage I and IIIand of 10% between stage I and REM stage. However, a transition towakefulness causes an increase of 22% of the HR response.

Another approach is a stochastic, Markov and semi-Markov, approach. Thehidden Markov models are automata with a finite state numberstochastically and non-deterministically describing a system. The basicstructure of a Markov model includes of a set of states S=(S1, S2 . . .SN) connected to each other by a probability defined in a transitiontable. The adjective “hidden” here translates the fact that the issuanceof observations from a state follows a random relationship and that theunderlying method (sleep stage) is not directly observable (it is“hidden”). This random characteristic of the measures which, added tothe properties of the Markov processes, provides the flexibility andpower of this approach. In the case of first-order models, the systemstate at time t depends only on the state of the system at time t-1,which defines a pure Markov process. Hidden semi-Markov models aresimilar to Markov models, but the system state at time t depends notonly on the state at t-1, but also of other parameters such as thelength of stay in the current state.

In the approach proposed here, each state of the Markov or semi-Markovmodel is a sleep stage and the probability of transition from one stageto another depends on both observable phenomenon (autonomic response)and on a transition probabilities matrix learned from a database, suchas that already established in the studies cited above. This type ofmodel estimates, given the observable phenomenon and the learnedtransition matrix, the state of a system at any time t.

Dependence of the kinesthetic stimulation based on sleep stages

The algorithm of FIGS. 8 and 9 shows an example of treatment ofrespiratory disorders of sleep apnea or hypopnea type per modulatedkinesthetic stimulation depending on the current sleep stage of thepatient, according to an exemplary embodiment.

The algorithm starts with the detection of the falling asleep of thepatient (step 54) according to a similar technique to the one describedabove in step 30 of FIG. 6 for the discrimination between the varioussleep stages. After the falling asleep is detected, the patient is nowin stage I, and the stimulation energy of the various stages are theninitialized (step 56).

A first technique may provide fixed values, progressively increasing asthe stages become deeper, to the stimulation energy of the differentstages. These values can be the same for all patients (values calculatedfrom averages of clinical observations), or can be individualized afterpreliminary assessment during polysomnography. These values can also beinitialized from a first efficient energy (calculated in step 42 in FIG.7) and then changes in relative variation (percentage) or absolutevariation (“delta”) of the first value for the other sleep stages can becalculated, these variations being directly collected from clinicalobservations.

Another technique is to apply the minimum stimulation as determined instep 42 of FIG. 7. When it is detected that the stage is changed, theenergy of the stimulation must be modified. If the stage is deeper,energy is increased to find a significant change in heart rateparameter. If the stage is lighter, the energy level starts from theminimum energy and back.

Specifically, the initialization step is illustrated in FIG. 9, once thesleep is detected (step 58 identical to step 54 of FIG. 8) a firststimulation is applied with the minimum energy (step 60). If ameasurable response is not detected (test 62), then the stimulationenergy is increased by one step (step 64) and the stimulation isrepeated until a measurable response is found. The energy thus adjustedis stored as the effective energy corresponding to stage I (step 66).The energies corresponding to the other stages are determined from thisvalue, either by adding a fixed value or by increasing it by apredetermined rate. During the initialization phase 56, we can alsodetermine the maximum stimulation energy value beyond which a wake is tobe feared and this for each sleep stage. This maximum value can bederived from energies evaluated for the different stages by adding apredetermined margin, or may have been determined in a priorpolysomnography.

Back to FIG. 8, once the initialization is completed (step 56), thealgorithm enters into a research phase of the emergence of a respiratorydisorder (step 68). Various methods of detection of the occurrence of anapnea or hypopnea has been described for example in EP 1319421 A1, EP1433496 A1 or EP 1584288 A1, all three in the name of Sorin CRM S.A.S,previously known as ELA Medical, each of which is incorporated herein intheir entireties.

These documents may be referred to for more details on the method tooperate the detection and diagnosis of sleep disorders. It is alsopossible, if the patient is not implanted, to use a nasal cannula (78 inFIG. 2) with an appropriate sensor for directly detecting theinterruption of the normal respiratory flow.

As soon as a condition is detected, the algorithm determines the currentsleep stage (step 70), this information being obtained in particular byimplementation of the algorithm described above with reference to FIGS.6 and 7. Kinesthetic stimulation is then delivered (step 72) with theenergy which had been determined for the current sleep stage, during theinitialization step 56. The effectiveness of kinesthetic stimulation isevaluated (step 74), that is to say, the device determines if thetherapy that has been applied has been effective or not. This efficiencycan be assessed during the event, immediately, that is to say it isobserved whether we are in the presence of a characteristic episode ofdebut of apnea followed by a rapid recovery of breathing revealing theapnea stop consecutive to kinesthetic stimulation.

Another method to evaluate the effectiveness of the therapy is,alternatively or in addition, to make a count of the number of eventsindicative of a respiratory disorder in a given period, for example 5 or10 minutes, and to check if, based on a history, this count indicates adecrease in the severity of symptoms or not.

In any event, if the therapy was not effective, the stimulation energyis increased by one step (step 76), and this up to a predeterminedmaximum corresponding to the limit that could cause a micro-awakening,therefore with the risk that the treatment itself produce deleteriouseffects.

The invention claimed is:
 1. A device for treating sleep apnea in apatient through stimulation, comprising: a generator configured toproduce stimulation pulses; a stimulator configued to receive thestimulation pulses produced by the generator and deliver stimulation tothe patient; and a controller configured to: detect a presence of sleepapnea; determine a sleep state of the patient; determine a response ofthe patient to the stimulation produced by the generator and aneffectiveness of the stimulation based on the response; adaptivelycontrol the generator based on the sleep state and the presence of thesleep apnea, wherein the sleep state includes a plurality of sleepstages; and modulate a stimulation energy of the stimulation pulsesproduced by the generator based on the sleep stage of the patient andthe presence of the sleep apnea, the controller configured to increasethe stimulation energy of the stimulation pulses in response to thestimulation pulses being ineffective in treating the sleep apnea to alevel sufficient to stop the sleep apnea and low enough to limit anoccurrence of micro-awakenings of the patient.
 2. The device of claim 1,wherein the controller is further configured to activate the generatorin the presence of the sleep state, and wherein the plurality of sleepstages include slow-wave sleep I, slow-wave sleep II, slow-wave sleepIII, slow-wave sleep IV, and REM sleep.
 3. The device of claim 1,wherein the controller is configured to increase the stimulation energyas the sleep stage increases, and decrease the stimulation energy as thesleep stage decreases.
 4. The device of claim 1, further comprising asensor configured to detect an occurrence of an apnea or hypopneaepisode, wherein the controller activates the generator upon detectionof the apnea or hypopnea episode.
 5. The device of claim 4, wherein thesensor is configured to detect an end of the apnea or hypopnea episode,wherein the controller disables the generator upon detection of the endof the apnea or hypopnea episode.
 6. The device of claim 1, wherein thecontroller modulates the stimulation energy based on a predeterminedincrement/decrement for each of the plurality of sleep stages.
 7. Thedevice of claim 1, wherein the controller utilizes a correspondencetable to assign the stimulation energy to each of the plurality of sleepstages.
 8. The device of claim 1, wherein the controller determines theresponse of the patient to the stimulation based on the variation of abiological parameter of the patient following the delivery of thestimulation to the patient, wherein the biological parameter is at leastone of a current heart rate of the patient, a respiratory rate, a bloodoxygen saturation, or a derivative parameter of a phonocardiographicsignal or an endocardial acceleration signal.
 9. The device of claim 8,wherein the controller is configured to determine a current sleep stagebased on the response of the patient to the stimulation.
 10. The deviceof claim 8, wherein the controller is configured to determine thestimulation energy that corresponds to a first sleep stage by:initializing the stimulation energy to a predetermined default minimumvalue; comparing a current response of the patient to a first threshold;iteratively changing the stimulation energy until the stimulation energyexceeds the first threshold; and storing the stimulation energy for thefirst sleep stage.
 11. The device of claim 10, wherein the controller isconfigured to determine and store the stimulation energy correspondingto each of the plurality of sleep stages following the first sleep stagebased on the stimulation energy stored for the first sleep stage.
 12. Amethod of treating sleep apnea in a patient through stimulation,comprising: detecting, by a controller, a presence of sleep apnea;determining, by the controller, a sleep state of the patient, whereinthe sleep state includes a plurality of sleep stages; determining, bythe controller, a response of the patient to stimulation pulses producedby a generator and an effectiveness of the stimulation pulses based onthe response; modulating, by the controller, a stimulation energy of thestimulation pulses produced by the generator based on the sleep stage ofthe patient and the presence of the sleep apnea, including increasingthe stimulation energy of the stimulation pulses in response to thestimulation pulses being ineffective in treating the sleep apnea to alevel sufficient to stop the sleep apnea and low enough to limit anoccurrence of micro-awakenings of the patient; and delivering, by astimulator, the modulated stimulation pulses received from the generatorto the patient.
 13. The method of claim 12, further comprisingactivating, by the controller, the generator in the presence of thesleep state, and wherein the plurality of sleep stages include slow-wavesleep I, slow-wave sleep II, slow-wave sleep III, slow-wave sleep IV,and REM sleep.
 14. The method of claim 12, wherein modulating thestimulation energy of the stimulation pulses comprises increasing thestimulation energy as the sleep stage increases, and decreasing, by thecontroller, the stimulation energy as the sleep stage decreases.
 15. Themethod of claim 12, further comprising: detecting, by a sensor, anoccurrence of an apnea or hypopnea episode; and activating, by thecontroller, the generator upon detection of the apnea or hypopneaepisode.
 16. The method of claim 15, further comprising: detecting, bythe sensor, an end of the apnea or hypopnea episode; and disabling, bythe controller, the generator upon detection of the end of the apnea orhypopnea episode.
 17. The method of claim 12, further comprisingdetermining, by the controller, the response of the patient to thestimulation pulses based on the variation of a biological parameter ofthe patient following the delivery of the stimulation pulses to thepatient, wherein the biological parameter is at least one of a currentheart rate of the patient, a respiratory rate, a blood oxygensaturation, and a derivative parameter of a phonocardiographic signal oran endocardial acceleration signal.
 18. The method of claim 17, furthercomprising determining, by the controller, a current sleep stage basedon the response of the patient to the stimulation pulses.
 19. The methodof claim 17, further comprising determining, by the controller, thestimulation energy that corresponds to a first sleep stage by:initializing the stimulation energy to a predetermined default minimumvalue; comparing a current response of the patient to a first threshold;iteratively changing the stimulation energy until the stimulation energyexceeds the first threshold; storing the stimulation energy for thefirst sleep stage; and determining and storing the stimulation energycorresponding to each of the plurality of sleep stages following thefirst sleep stage based on the stimulation energy stored for the firstsleep stage.
 20. A device for treating sleep apnea in a patient,comprising: a generator configured to produce stimulation pulses; astimulator configured to receive the stimulation pulses produced by thegenerator and deliver stimulation to the patient; and a controllerconfigured to: determine a response of the patient to the stimulationpulses produced by the generator and an effectiveness of the stimulationpulses based on the response; and modulate a stimulation energy of thestimulation pulses produced by the generator based on a sleep stage ofthe patient during a sleep apnea or hypopnea episode, the controllerconfigured to increase the stimulation energy of the stimulation pulsesin response to the stimulation pulses being ineffective in treating thesleep apnea or hypopnea episode to a level sufficient to stop the sleepapnea or hypopnea episode and low enough to limit an occurrence ofmicro-awakenings of the patient.